The tenet of this application is that progress in biomedical research is increasingly dependent upon high throughput biotechnological advances (e.g., high throughput "next generation" DNA sequencing, analysis of genomic data for variants, cross-genome comparisons, statistical simulations, protein folding, imaging, electron microscopic structure determination, molecular dynamics, structural biology, high-throughput drug screening, and proteomics) that are increasingly limited by the inability of the "personal computers" and small departmental clusters available to Yale investigators to adequately and timely analyze the enormous volume of the resulting data. The inexorable trend toward the use of higher throughput technologies in biomedical research that produce ever more massive data sets has resulted in substantially increasing the use of the Yale Biomedical High Performance Computing (HPC) Center such that its instrumentation can no longer meet the surging demand. While recent biotechnological breakthroughs have brought us to the exciting threshold of systems level biomedical research, to take advantage of these technologies Yale investigators will need access to far more powerful high performance computers than are now within the HPC Center and a commensurate level of technical programming and systems administration support. The requested high performance computing instrumentation would enable the Yale Biomedical HPC Center to meet the ever increasing need for bringing more powerful computers to bear on challenging, yet amenable problems that stand in the way of biomedical research. The strengths of this application include the very diverse and productive investigator user base that would Continue to support the Biomedical HPC Center, the almost 30 years of demonstrated ability of the Keck Laboratory to oversee and continually operate and maintain sophisticated biotechnological instrumentation and to bring it within reach of hundreds of Yale and non-Yale researchers, the extensive infrastructure and expertise that is available to bring the requested instrumentation on-line and to oversee and support its continuous use, the demonstrated success of the Biomedical HPC Center that would house the requested instrumentation, and the careful planning and very firm support of both Yale University and its School of Medicine to ensure that this application represents a coordinated and well conceived institutional response to the challenge of providing the high performance computing needed to continue to drive biomedical research forward. PUBLIC HEALTH RELEVANCE: If this application is funded, the requested High Performance Computing instrumentation would provide biomedical researchers'with sufficient shared computing power to analyze the vast amounts of data that will be collected across the Yale campus by an ever increasing number of laboratories using state-of-the-art high throughput DNA sequencing, proteomics, and other technologies. The results of the proposed research would make a very substantial contribution to biomedical research that would extend to and increase our knowledge of embryonic development, epigenetic, hematopoietic differentiation, inflammation, metastasis, protein elasticity, protein folding;infectious diseases such as HIV and influenza, and non-infectious diseases such as hypertension, cancer, diabetes, renal diseases, asthma, amyloid diseases, coronary artery disease, drug addiction, dyslexia, emphysema, and glaucoma. Job Creation Funding of this application would commit Yale University and its Medical School (see attached support letters) to maintaining three years of employment for one Systems administration staff (annual cost is $125,000) and four Ph.D.-level staff, two each in the Keck Laboratory's HPC and Bioinformatics Resources (annual subsidy is $600,000) for a three year total of $2,175,000. Environmental Impact We believe that electrical use/CPU-hr of computing time is less on the requested HPC instrumentation than it is on the existing instrumentation that would be replaced if this application is funded.